CN114105972A - Xinkening derivative and application thereof in preparation of high-optical-purity indoxacarb intermediate - Google Patents
Xinkening derivative and application thereof in preparation of high-optical-purity indoxacarb intermediate Download PDFInfo
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- C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
- C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
- C07D453/04—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems having a quinolyl-4, a substituted quinolyl-4 or a alkylenedioxy-quinolyl-4 radical linked through only one carbon atom, attached in position 2, e.g. quinine
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Abstract
The invention discloses a novel cinchona alkaloid, namely a novel cinchonine derivative which is easy to prepare, low in cost and high in efficiency, and the catalytic efficiency, the target product yield and the enantioselectivity of cinchona alkaloid organic catalysts such as cinchonine and the like in the asymmetric alpha-hydroxylation reaction of a 5-chloro-1-indanone-2-methyl formate intermediate are greatly improved by amidating and derivatizing a hydroxyl at the C-9 position of cinchonine. The S isomer content of the 5-chloro-2-methoxycarbonyl-2-hydroxy-1-indanone is improved to more than 90 percent from 50 percent when the cinchonine is used as the catalyst, and the catalyst has the advantages of simple synthesis process, small catalyst dosage and low cost, is beneficial to industrial production and provides high-quality indoxacarb products.
Description
Technical Field
The invention belongs to the technical field of asymmetric catalytic synthesis, and particularly relates to a novel cinchonine derivative and application thereof in preparation of a high-optical-purity indoxacarb intermediate.
Background
Indoxacarb (Indoxacarb) is a carbamate pesticide with an oxadiazine structure, which is developed by DuPont, the molecule of the Indoxacarb contains a chiral C atom, and the Indoxacarb has two configurations of R and S, but only the S-configuration has insecticidal activity. In the indoxacarb products sold in the global market at present, the S/R ratio is 1/1 (raceme), 3/1, 9/1, 99 and 1 (high-end products), the demand is about 3500 tons/year, the capacity can only reach 1500 tons/year, and the current production process technology is relatively backward, so that the possibility of expanding the production capacity is limited, and the development of high-efficiency indoxacarb products (high optical purity) has important economic value and social benefit.
The current development aiming at the indoxacarb synthetic route is mainly focused on asymmetric hydroxylation reaction, and the (S) -5-chloro-2-methoxycarbonyl-2-hydroxy-1-indanone is prepared by asymmetric alpha-hydroxylation reaction of a 5-chloro-indanone methyl formate intermediate, and the used catalysts mainly comprise novel cinchona alkaloid derivatives, chiral phosphine Schiff bases-Cu (I), tartaric acid derived chiral guanidine, chiral Salen-Zr complexes, chiral Zr-Salen polymers, S-timolol derivatives, aryloxy beta-aminoalcohol compounds and the like, but the methods have the problems of harsh reaction conditions, high stability, toxicity and cost, unsatisfactory catalytic effect (ee value and yield) and the like in the preparation of the catalysts.
The DuPont uses cinchona alkaloid cinchonine as a catalyst in 2000 industrial production, and is applied to the asymmetric alpha-hydroxylation reaction of a 5-chloro-indanone methyl formate intermediate to obtain an ee value of 50% and a yield of 85%. Since then, the prior art reports a large number of novel cinchona-alkaloid derivatives for use as catalysts in the alpha-hydroxylation reaction of this step. Although structural derivation based on cinchona alkaloid has been a hot issue in order to provide a highly efficient catalyst, according to the prior art report and the experimental research results of the inventor, the various catalysts developed based on structural derivation of cinchona alkaloid, even with very similar structures, still have uncertainty in catalytic performance corresponding to the α -hydroxylation reaction in terms of reaction efficiency, yield, enantioselectivity and the like (see, for example, CN103333069A, CN108129306A, CN110511217A and the like), or even cannot catalyze the reaction (see, "research based on asymmetric organic catalytic oxidation of drug source framework", yuanchun, university of chui, major university of continuos university academic position paper). The inventor is engaged in the research of asymmetric organic catalysts of cinchona alkaloids for a long time, tries to synthesize hundreds of cinchona alkaloid derivatives, tests the catalytic performance of the cinchona alkaloid derivatives on alpha-hydroxylation reaction, and successfully screens three novel cinchonine derivatives with high-efficiency catalytic activity, thereby obtaining the invention.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a novel cinchonine derivative which is easy to prepare, low in cost and high in efficiency, and the catalytic efficiency, the target product yield and the enantioselectivity of cinchonine alkaloid organic catalysts such as cinchonine and the like in the asymmetric alpha-hydroxylation reaction of a 5-chloro-1-indanone-2-methyl formate intermediate are greatly improved by carrying out amidation derivatization on hydroxyl at the C-9 position of cinchonine. The S isomer content of the 5-chloro-2-methoxycarbonyl-2-hydroxy-1-indanone is improved to more than 90 percent from 50 percent when the cinchonine is used as the catalyst, and the catalyst has the advantages of simple synthesis process, small catalyst dosage and low cost, is beneficial to industrial production and provides high-quality indoxacarb products.
As a first aspect of the present invention, the present invention provides a novel class of cinchonine derivative catalysts having the structural formula:
The novel cinchonine derivative catalyst provided by the invention has a specific structure shown in the following formulas 1a to 1 c:
as a second aspect of the present invention, the present invention provides a method for preparing a novel cinchonine derivative catalyst having the structure shown above, comprising the steps of:
the first synthetic route is as follows: the cinchonine reacts with dimethylcarbamoyl chloride under basic conditions to prepare a novel cinchonine derivative catalyst represented by formula 1 a:
the second synthetic route is as follows: the cinchonine reacts with an R' substituted isocyanate compound under the alkaline condition to prepare a novel cinchonine derivative catalyst shown in a formula 1b and/or 1 c:
wherein R' is cyclohexyl, 3, 4-dichlorophenyl.
According to the preparation method of the novel cinchonine derivative catalyst with the structure shown in the invention, in the first route and the second route, in the alkaline condition, the alkali is selected from any one or more of sodium hydride, sodium tert-butoxide, sodium methoxide, sodium hydroxide, potassium hydroxide, triethylamine and potassium carbonate; preferably, the base is sodium hydride. The feeding amount of the alkali is 1-3 molar equivalents of the feeding amount of the cinchonine, and preferably 1-1.5 molar equivalents.
According to the preparation method of the novel cinchonine derivative catalyst with the structure, in the first route, the feeding molar ratio of cinchonine to dimethylcarbamoyl chloride is 1: 1-3, and preferably 1: 1.5-2. In the second route, the feeding molar ratio of the cinchonine to the R' substituted isocyanate compound is 1: 1-3, and preferably 1: 1.5-2.
According to the preparation method of the novel cinchonine derivative catalyst with the structure, in the first route and the second route, the reaction temperature is-20 ℃, preferably-5-0 ℃, and the reaction time is 2-24 hours, preferably 5-12 hours.
As a third aspect of the invention, the invention provides application of a novel cinchonine derivative catalyst based on structures shown in formulas 1a to 1c in the asymmetric alpha-hydroxylation reaction of beta-keto ester compounds, in particular application in the asymmetric alpha-hydroxylation reaction of a 5-chloro-1-indanone-2-methyl formate intermediate to prepare (S) -5-chloro-2-methoxycarbonyl-2-hydroxy-1-indanone.
According to the application, the (S) -5-chloro-2-methoxycarbonyl-2-hydroxy-1-indanone can be prepared with excellent yield and enantioselectivity, and the ee percent is more than or equal to 90%.
The application method of the novel cinchonine derivative catalyst in the preparation of (S) -5-chloro-2-methoxycarbonyl-2-hydroxy-1-indanone by the asymmetric alpha-hydroxylation reaction of a 5-chloro-1-indanone-2-methyl formate intermediate is as follows:
adding 5-chloro-1-indanone-2-methyl formate, a novel cinchonine derivative catalyst with a structure shown in formulas 1a to 1c and an organic solvent into a reactor in sequence, dripping a peroxide oxidant under the condition of stirring and cooling, continuing to keep the temperature and stir until the reaction is complete after the dripping is complete, and obtaining (S) -5-chloro-2-methoxycarbonyl-2-hydroxy-1-indanone through aftertreatment. The reaction formula is as follows:
according to the application method, the dosage of the novel cinchonine derivative catalyst with the structure shown in the formulas 1a to 1c is 0.01 to 0.05 molar equivalent, preferably 0.02 to 0.03 molar equivalent relative to the dosage of the 5-chloro-1-indanone-2-methyl formate.
According to the application method of the invention, the peroxide oxidant is selected from any one of tert-butyl peroxide and cumene hydroperoxide, preferably tert-butyl peroxide; the amount of the peroxide oxidant is 1 to 1.5 molar equivalents, preferably 1 to 1.2 molar equivalents, relative to the amount of the methyl 5-chloro-1-indanone-2-carboxylate. The organic solvent is selected from one or more of toluene, xylene, chlorobenzene, dichloromethane, ethyl acetate and chloroform; toluene is preferred.
According to the application method, the cooling and reaction temperature is-20 ℃, and preferably-5-0 ℃; the reaction time is 4-24 h, preferably 6-12 h.
In conclusion, the novel cinchonine derivative catalyst provided by the invention can be used for preparing the indoxacarb synthetic intermediate- (S) -5-chloro-2-methoxycarbonyl-2-hydroxy-1-indanone with the S isomer content of more than or equal to 90 percent, and has remarkably improved enantioselectivity and good yield of a target product compared with the conventional methods using cinchonine and the like as catalysts (such as the industrial method of DuPont company, CN105461552A and CN 103333069A). The novel cinchonine derivative catalyst disclosed by the invention is low in dosage, high in catalytic efficiency, low in time consumption and high in catalytic efficiency. The novel cinchonine derivative catalyst provided by the invention is simple in preparation method, can be obtained by directly taking cinchonine as a raw material and performing one-step simple reaction derivatization, is simple in preparation process and low in price, is suitable for industrial mass production, and is beneficial to providing high-quality indoxacarb products.
Drawings
Fig. 1 is a nuclear magnetic hydrogen spectrum of the catalyst 1 a.
Fig. 2 is a nuclear magnetic hydrogen spectrum of the catalyst 1 b.
FIG. 3 is a nuclear magnetic hydrogen spectrum of the catalyst 1 c.
Detailed Description
The foregoing and other objects of the present invention will be apparent from the following more particular description of the invention, as illustrated in the accompanying drawings and described in the specification, which is by way of example, with reference to the accompanying drawings. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention. The following examples are carried out using conventional prior art techniques, except as otherwise specified.
Example 1 preparation of (S) -quinolin-4-yl ((1S,2S,4S,5R) -5-vinylquinuclidin-2-yl) methyldimethylcarbamate (1a)
Adding 205ml of anhydrous tetrahydrofuran and 10.0g (34.0mmol) of cinchonine into a 1000ml three-neck glass bottle under the protection of nitrogen, cooling to 5 ℃, adding 60% NaH2.72g (54.7mmol) in batches, stirring for 30min under heat preservation, dropwise adding DMCC 6.58g (61.2mmol), stirring for 5h at room temperature, adding 250g of ice water and 400ml of ethyl acetate, separating out the water phase, extracting once with 200ml of ethyl acetate, combining the ethyl acetate phases without adding ethyl acetateDrying with MgSO4 water, filtering, evaporating the solvent, and carrying out silica gel column chromatography with 200-300 mesh to obtain 7.45g of light yellow solid with yield of 60%.1HNMR(600MHz,CH3OH-d4):δ8.84(t,J＝6Hz,1H),8.31(d,J＝6.0Hz,1H),8.08(d,J＝6.0Hz,1H),7.80-7.78(t,J＝6Hz,1H),7.71-7.69(t,J＝6Hz,1H),7.57(t,J＝56Hz,1H),6.58(d,J＝6.0Hz,1H),6.11-6.04(m,1H),5.14-5.11(m,2H),4.89(s,1H),3.40-3.36(m,1H),3.12(s,12H),2.85(s,2H),2.80(s,1H),2.73-2.71(m,1H),2.37-2.33(m,1H),2.04-2.00(m,1H),1.82(s,1H),1.59-1.57(m,2H),1.53-1.51(m,1H),1.28(s,2H),0.96-0.94(m,1H)。
Example 2 preparation of (S) -quinolin-4-yl ((1S,2S,4S,5R) -5-vinylquinuclidin-2-yl) methylcyclohexaneamino carbonate (1b)
Adding 205ml of anhydrous tetrahydrofuran and 10.0g (34.0mmol) of cinchonine into a 1000ml three-neck glass bottle under the protection of nitrogen, cooling to 5 ℃, adding 60% NaH2.72g (54.7mmol) in batches, stirring for 30min under heat preservation, dropwise adding 7.66g (61.2mmol) of cyclohexyl isocyanate, stirring for 10h at room temperature, adding 250g of ice water and 400ml of ethyl acetate, separating out the water phase, extracting once with 200ml of ethyl acetate, combining the ethyl acetate phases, drying with anhydrous MgSO4, filtering, evaporating the solvent, and performing silica gel column chromatography with 200-300 mesh to obtain 7.27g of light yellow solid with the yield of 51%. 1HNMR (600MHz, CH3OH-d4): δ 8.83(d, J ═ 6.0Hz,1H),8.31(d, J ═ 6.0Hz,1H),8.08(d, J ═ 6.0Hz,1H),7.81-7.79(t, J ═ 6Hz,1H),7.71-7.68(t, J ═ 9Hz,1H),7.59(d, J ═ 6.0Hz,1H),6.58(d, J ═ 6.0Hz,1H),6.20-6.14(m,1H),5.13-5.11(m,2H),4.89(s,6H),3.02-2.99(m,1H),2.90-2.86(m,1H),2.79(m,1H), 2.70(m,1H), 1.72 (m,1H), 1H), 1.06-2.06 (m,1H), 1H, 1.72 (m,1H), 2H) ..
Example 3 preparation of (S) -quinolin-4-yl ((1S,2S,4S,5R) -5-vinylquinuclidin-2-yl) methyl- (3, 4-dichlorophenylamino) carbonate (1c)
Adding 205ml of anhydrous tetrahydrofuran and 10.0g (34.0mmol) of cinchonine into a 1000ml three-neck glass bottle under the protection of nitrogen, cooling to 5 ℃, adding 60% NaH2.72g (54.7mmol) in batches, stirring for 30min under heat preservation, dropwise adding 11.5g (61.2mmol) of 3, 4-dichlorophenyl isocyanate, stirring for 10h at room temperature, then adding 250g of ice water and 400ml of ethyl acetate, separating out a water phase, extracting once with 200ml of ethyl acetate, combining ethyl acetate phases, drying with anhydrous MgSO4, filtering, evaporating the solvent, and carrying out 200-300 mesh silica gel column chromatography to obtain 7.54g of light yellow solid with the yield of 46%. 1H-NMR (600MHz, CH3OH-d4): δ 8.85(d, J ═ 6.0Hz,1H),8.37(d, J ═ 6.0Hz,1H),8.09(d, J ═ 6.0Hz,1H),7.81-7.64(m,1H),7.38(d, J ═ 6.0Hz,1H),7.33(t, J ═ 12.0Hz,1H),6.66(d, J ═ 6.0Hz,1H),6.16(s,1H),5.12(m,2H),3.40(m,1H),3.01-2.98(m,1H),2.77(m,1H),2.72-2.69(m,1H), 2.32(m,1H),2.16-2.12(m,1H),1.75 (m,1H), 1.53-1H), 1.14(m,1H), 1H), 1.14-1H, 1.14(m,1H), 1H, 1.14, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1.
Preparation of methyl (S) -5-chloro-2-hydroxy-1-indanone-2-carboxylate using example 1
Under the protection of nitrogen, adding 80.7g (0.36mol) of 5-chloro-1-indanone-2-methyl formate into a 1000ml three-mouth glass bottle, adding 650g of toluene and 3.1g (2.4 mol%) of catalyst 1a, stirring and cooling to 0 ℃, dropwise adding 35.6g (0.39mol) of tert-butyl peroxy alcohol (TBHP) under heat preservation, continuing stirring and mixing for 12h after the dropwise adding is finished, washing with 10% NaHCO3, washing with water, and concentrating to a product of 50%; cooling to 0 ℃, keeping the temperature and stirring for 2h, filtering, leaching a filter cake with toluene, and drying to obtain 73.5g of a product with the yield of 85.0 percent and 92.5 percent ee (S).
Preparation of methyl (S) -5-chloro-2-hydroxy-1-indanone-2-carboxylate using example 2
Under the protection of nitrogen, adding 80.7g (0.36mol) of 5-chloro-1-indanone-2-methyl formate into a 1000ml three-mouth glass bottle, adding 650g of toluene and 3.6g (2.4 mol%) of catalyst 1b, stirring and cooling to-5 ℃, dropwise adding 38.9g (0.43mol) of tert-butyl peroxy alcohol (TBHP) under heat preservation, continuing stirring and mixing for 12h after dropwise adding, washing with 10% NaHCO3, washing with water, and concentrating to a product of 50%; cooling to 0 ℃, preserving heat and stirring for 2h, filtering, leaching filter cakes with toluene, and drying to obtain 78.6g of a product with the yield of 90.9 percent and the ee (S) of 99.1 percent.
Preparation of methyl (S) -5-chloro-2-hydroxy-1-indanone-2-carboxylate using example 3
Under the protection of nitrogen, adding 80.7g (0.36mol) of 5-chloro-1-indanone-2-methyl formate into a 1000ml three-mouth glass bottle, adding 650g of toluene and 4.2g (2.4 mol%) of catalyst 1c, stirring and cooling to 0 ℃, dropwise adding 38.9g (0.43mol) of tert-butyl peroxy alcohol (TBHP) under heat preservation, continuing stirring and mixing for 12h after the dropwise adding is finished, washing with 10% NaHCO3, washing with water, and concentrating to a product of 50%; cooling to 0 ℃, preserving heat and stirring for 2h, filtering, leaching a filter cake with toluene, and drying to obtain 71.4g of a product with the yield of 82.6 percent and 93.2 percent ee (S).
Claims (10)
1. A cinchonine derivative catalyst having the following structural formula:
2. The method of preparing a cinchonine derivative catalyst as claimed in claim 1, comprising the steps of:
the first synthetic route is as follows: reacting cinchonine with dimethylcarbamoyl chloride under basic conditions to prepare a cinchonine derivative catalyst represented by formula 1 a:
the second synthetic route is as follows: the cinchonine reacts with an R' substituted isocyanate compound under the alkaline condition to prepare a cinchonine derivative catalyst shown in a formula 1b and/or 1 c:
wherein R' is cyclohexyl, 3, 4-dichlorophenyl.
3. The method according to claim 2, wherein in the alkaline conditions of the first and second schemes, the base is selected from any one or more of sodium hydride, sodium tert-butoxide, sodium methoxide, sodium hydroxide, potassium hydroxide, triethylamine and potassium carbonate; preferably, the base is sodium hydride; the feeding amount of the alkali is 1-3 molar equivalents of the feeding amount of the cinchonine, and preferably 1-1.5 molar equivalents.
4. The preparation method according to claim 2, wherein in the first route, the charging molar ratio of the cinchonine to the dimethylcarbamoyl chloride is 1: 1-3, preferably 1: 1.5-2; in the second route, the feeding molar ratio of the cinchonine to the R' substituted isocyanate compound is 1: 1-3, and preferably 1: 1.5-2.
5. The method according to claim 2, wherein in the first and second routes, the reaction temperature is-20 to 20 ℃, preferably-5 to 0 ℃, and the reaction time is 2 to 24 hours, preferably 5 to 12 hours.
6. The use of the cinchonine derivative catalyst of claim 1 in asymmetric alpha-hydroxylation of beta-keto ester compounds.
7. The use of claim 6 in the preparation of (S) -5-chloro-2-methoxycarbonyl-2-hydroxy-1-indanone by the asymmetric alpha-hydroxylation reaction of a methyl 5-chloro-1-indanone-2-carboxylate intermediate.
8. The application according to claim 7, wherein the application method is as follows:
sequentially adding 5-chloro-1-indanone-2-methyl formate, a cinchonine derivative catalyst and an organic solvent into a reactor, dropwise adding a peroxide oxidant under the condition of stirring and cooling, continuing to keep the temperature and stir for reaction till the reaction is complete after the dropwise adding is complete, and obtaining (S) -5-chloro-2-methoxycarbonyl-2-hydroxy-1-indanone after post-treatment; the reaction formula is as follows:
9. the use according to claim 8, wherein the amount of the cinchonine derivative catalyst is 0.01 to 0.05 molar equivalent, preferably 0.02 to 0.03 molar equivalent, relative to the amount of the 5-chloro-1-indanone-2-carboxylic acid methyl ester.
10. The use according to claim 8, wherein the peroxide-based oxidizing agent is any one selected from t-butyl peroxide and cumene hydroperoxide, preferably t-butyl peroxide; the organic solvent is selected from one or more of toluene, xylene, chlorobenzene, dichloromethane, ethyl acetate and chloroform, and toluene is preferred; the cooling and reaction temperature is-20 to 20 ℃, and preferably-5 to 0 ℃; the reaction time is 4-24 h, preferably 6-12 h.
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| CN115806504A (en) * | 2022-12-12 | 2023-03-17 | 合肥工业大学 | Asymmetric chiral ligand, preparation method thereof, prepared catalyst, synthesis method and application |
Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997046557A1 (en) * | 1996-06-05 | 1997-12-11 | Wolfgang Lindner | Cinchonan based chiral selectors for separation of stereoisomers |
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| CN113563187A (en) * | 2021-08-20 | 2021-10-29 | 南京工业大学 | Preparation method of chiral alpha-hydroxy-beta-keto ester compound |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN115806504A (en) * | 2022-12-12 | 2023-03-17 | 合肥工业大学 | Asymmetric chiral ligand, preparation method thereof, prepared catalyst, synthesis method and application |
| CN115806504B (en) * | 2022-12-12 | 2024-04-16 | 合肥工业大学 | Asymmetric chiral ligand and preparation method thereof, prepared catalyst, synthesis method and application |
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